The objectives of this study are to determine functional roles for recurrent cytogenetic lesions in a mouse B lymphoid cancer model, and to elucidate the mechanisms for formation of characteristic karyotypic instability. While genomic instability is a recognized hallmark, many tumors, including lymphomas and leukemias, the molecular mechanisms behind genomic instability, as well as its consequences, are poorly understood. Cytogenetic abnormalities affecting chromosomes 4q21 or 11q23 are common in lymphoid malignancies, such as mantle cell lymphoma and preB-ALL, the latter being the most common pediatric malignancy, at nearly 25% of all childhood cancer diagnoses. Translocations involving 11q23, producing oncogenic fusions of the MLL gene with numerous possible partners, are common;other abnormalities, such as amplification at 4q21 and/or deletion of 11q23, though less frequent, also occur. Rearrangements at 11q23 generally predict a poor prognosis, especially in infant B-ALL patients, and malignancies with deletions at 11q23 tend to exhibit greater karyotypic instability than those with balanced translocations in the same region. Deletions at 11q23 are also associated with Richter's syndrome, characterized by the transformation of chronic lymphocytic leukemia to high-grade non-Hodgkin's Lymphoma (NHL). Richter's syndrome leads to accelerated tumor growth, clinical deterioration, and resistance to conventional therapy. Emerging evidence suggests that defects in DNA double strand break repair can lead to oncogenic genome instability and, in support of this notion, mutations in DNA break repair factors are implicated in a number of human tumors, including Richter's syndrome. Mice deficient for any of the six known components of the nonhomologous end joining pathway of DNA break repair, and for the tumor suppressor p53 (encoded by Trp53;collectively referred to as NHEJ/Trp53 mice), develop aggressive, multi-focal progenitor (pro)-B cell lymphomas with extremely high penetrance. Strikingly, copy number abnormalities (CNA) observed on chromosomes 5 (CNA5) and 9 (CNA9) in Lig4/Trp53 tumors affect regions related to human 4q21 and 11q23, respectively. Thus, NHEJ/Trp53 mice provide an animal model for lymphoid cancers with CNA-type lesions at these chromosomal locations, and will yield insights into currently unknown facets of human lymphoid cancers, such as childhood B-ALL and Richter's syndrome. These studies will therefore lay a foundation for the development of improved diagnostic methods, as well as the formulation and clinical development of new, possibly individualized, therapeutic approaches.